Metastasis, the primary cause of cancer mortality is a complex process with multiple steps that include tumour cell invasion, intravasation, extravasation, and establishment of secondary tumours in distant organs1. For breast cancer, genomic analysis of primary tumours and metastases from patients has identified sets of genes whose expression appear to be prognostic of outcome2-4. In addition, this type of analysis has led to sub-classification of human breast cancers into intrinsic subtypes that can also predict outcome and therapeutic response2-5. Despite this significant progress, the functions of genes within these classifications, and whether they are drivers of tumour progression or simply bystander markers, remains unclear. Furthermore, the molecular properties of primary tumours that dictate metastatic potential versus those that do not, have not been defined.
For breast cancer, several potential candidate metastasis genes have been identified for organ-specific metastasis to the bone, lungs and brain6. For lung metastasis, the collective expression of genes such as epiregulin, MMP-1 and -2, and Cox-27, have been found to be causative in promoting metastasis. CAIX has also been implicated in breast cancer.
For instance, U.S. Pat. No. 6,297,051 discloses that abnormal expression of CAIX may signal oncogenesis, and accompanying diagnostic and prognostic methods. Therapeutics targeted to the CAIX gene or protein are contemplated.
U.S. Patent Publication 2004/0146955 discloses methods for inhibiting the growth of preneoplastic and neoplastic vertebrate cells with abnormal expression of carbonic anhydrase-9 (CAIX). Specific CAIX inhibitors are disclosed.
Pastorekov & Z'vada (Cancer Therapy 2, 245-262 (2004)) suggest CAIX as a therapeutic target for cancer treatment.
Brenna, D. J. et al. (Clinical Cancer Research 12(21), 6421-6431 (2006)) disclose CAIX as a prognostic marker in premenopausal breast cancer patients.
U.S. Patent Publication 2008/0095707 discloses therapeutic methods for inhibiting the growth of neoplastic cells that abnormally express CAIX, for example, with CAIX inhibitors. Screening methods for identification of compounds which inhibit CAIX are contemplated.
U.S. Pat. No. 7,378,091 discloses monoclonal and polyclonal antibodies directed against CAIX which may be used in diagnosis or treatment of disorders associated with increased activity of CAIX, including cancers.
However, other genes which drive metastasis or dictate tumour grade (including metastatic potential) remain unknown. It would, therefore, be desirable to identify new or improved indicators of tumour metastatic potential. It would be advantageous to develop diagnostic or prognostic indicators capable of identifying tumours of moderate or high metastatic potential or of discriminating between tumours of differing metastatic potentials.